There is limited understanding of the mechanism of uremic growth failure, which involves both skeletal elongation and calorie storage, and transcends attribution to hormonal or nutritional deficiency. Skeletal growth entails cartilage stimulation by somatomedins, circulating factors with broad anabolic effects. Inhibitors limit the actions of somatomedins; bioassay measurements of net somatomedin activity reflect both somatomedins and inhibitors. Net somatomedin activity is low in uremia, due apparently to increases in a low-MW inhibitor(s). The inhibitor appears to be a peptide, and a factor of similar size is found in urine. Preliminary studies indicate that the inhibitor has broad antianabolic effects. These observations suggest that many growth-related metabolic aspects of the uremic syndrome could be due to the accumulation in the circulation of a "uremic somatomedin inhibitor", but we have almost no information about the nature of the inhibitor, and only partial knowledge about the ways in which the inhibitor might impair growth. To elucidate underlying mechanisms, we propose: 1) To examine the biochemical basis for the inhibitory activity, (a) the inhibitor in human plasma will be isolated and characterized physicochemically, (b) the biochemical characteristics of the inhibitor found in urine will be compared to those of the circulating inhibitor, and (c) development of an immunoassay for the inhibitor will be attempted. 2) To assess potential contributions to disordered metabolism, (a) the biological actions of the purified inhibitor will be examined in tissue models of skeletal elongation and calorie storage, (b) the mechanism of antagonism of somatomedin and insulin action will be studied in terms of reversibility, kinetics, and temporal sequence of effects, and (c) effects on insulin binding will also be tested. 3) To pursue the hypothesis that accumulation of a "somatomedin" inhibitor in renal failure is a likely basis for decreases in calorie storage as well as skeletal elongation, (a) the relative antagonism of insulin and somatomedin action will be compared as isolation progresses, and (b) size profiles of circulating anti-insulin and anti-somatomedin activity will be related to immunoassayable inhibitor in progressive stages of renal failure; combined efforts will either link the "somatomedin" inhibitor to insulin resistance in uremia, or point to other factors which affect calorie storage but not skeletal elongation. These studies should improve understanding of the pathophysiology of impaired growth in uremia, and may lead to new concepts for therapy in children and adults with renal failure.